Since the initial reports about heparin [Howell et al, Am. J. Physiol. 47, 328 (1918)] and bishydroxycoumarin or dicumarol [Link, Harvey Lect., 39, 162-216(1944)], anticoagulants have become the object of extensive biological investigation. Heparin is still considered by many as the drug of choice, despite the fact that it is not well absorbed orally and must be administered by a parenteral route. Toxic side effects are uncommon, but parenteral administration, whether as intermittent injections or continuous infusion, precludes its long term use. Therapy employing the clinically used oral anticoagulants, on the other hand, is difficult to control between desired limits because of the considerable variability in their rates of metabolism under differing conditions. In addition to undesirable delay in onset of activity after administration, drug interaction problems and side effects make the oral anticoagulants which are now available poor substitutes for heparin itself.
The possibility of administering heparin by routes other than injection while obtaining results comparable to those obtained by injection has aroused the interest of many investigators. See, for example, Windsor et al, Nature, London, 190, 263 (1961); Teow Yan Koh, U.S. Pat. Nos. 3,482,014, 3,510,561 and 3,548,052; and Teow Yan Koh et al, U.S. Pat. Nos. 3,506,642 and 3,577,534. Notably, orally active heparin salts and complexes have been described in the patent literature, e.g. amines, amides (the aforementioned Teow Yan Koh patents) and acid salts such as Na, K, Li etc. (the aforementioned Teow Yan Koh et al patents). Attempts have also been made to enhance oral absorption using sulfoxides and sulfones.
Nevertheless, serious need exists in this art for improved oral delivery of heparin.